Clinical outcomes of presbyopia-correcting intraocular lenses in patients with Fuchs endothelial corneal dystrophy

Fuchs endothelial corneal dystrophy (FECD) is considered a contraindication for the implantation of presbyopia-correcting IOLs, without sufficient corroborating evidence. A Retrospective, case–control study. Nineteen eyes of ten patients with grade 2–5 FECD (study group) and 57 healthy eyes of 57 patients (control group) who underwent cataract surgery with implantation of presbyopia-correcting IOLs, at the Ein-Tal Eye Center, Tel Aviv, Israel, were included. The target refraction was emmetropia for both groups. Two subgroups of IOLs were analyzed separately: extended depth of focus (EDOF), (9 eyes of FECD patients and 27 eyes of control patients) and multifocal IOLs (10 eyes of FECD patients and 30 eyes of control patients). Main outcome measures were visual acuity and refraction 6 weeks after the surgery. Secondary outcomes were patient perceptions of visual acuity, spectacle independence, photic phenomena and satisfaction scores, reported in a self-assessment questionnaire. FECD patients in the EDOF IOL subgroup had inferior uncorrected distance visual acuity (P = 0.007) and better uncorrected near visual acuity (P = 0.001) compared to the controls. They had less spectacle independence for the intermediate range (P = 0.01) and overall (P = 0.006). However, they did not have more photic phenomena. In the multifocal IOL subgroup, no significant differences were found between the FECD and the control group in visual acuity for all ranges and in spectacle independence. FECD patients had more photic phenomena than the controls (P = 0.006), but it did not interfere with daily life activities. There was no difference in post-operative mean spherical equivalent, patient reported visual perception, and general satisfaction between FECD and control patients in both groups. Our results suggest that presbyopia-correcting IOLs can be carefully considered in patients with grade 2–5 FECD, with slightly inferior results compared with healthy eyes.

Statistical analysis. Data were analyzed using the SPSS software (version 21.0; IBM Corp., Armonk, NY).
The Mann-Whitney U test was used to compare continuous variables between the two groups. Centroid astigmatism was analyzed by its double angled X and Y axis components. Paired Hotelling's T-squared test was used for bivariate statistical analysis, as described by Naeser 9 and indicated by Abulafia et al. 10 Pearson's Chi-Square or Fisher's exact test, as indicated, were used for categorical variables. ANOVA test was used for multivariate regression analysis. Patient feedback from the survey was expressed as proportions and assessed as categorical variables. For analysis, positive outcomes regarding spectacle use were attributed to the answers "Never" and "Rarely". For questions regarding quality of vision, the answers "Good" and "Excellent" were considered indicative of high patient satisfaction. Photic phenomena were attributed to answers graded "Often" or "All the time" and overall patient satisfaction was graded as positive if the patient would choose or probably choose the same

Results
A total of 19 eyes of 10 patients with FECD were included in the study (each eye was considered separately). The statistical power based on post hoc power analysis was 0.6. The mean endothelial cell count was 1,323.52 ± 767.54 cells/mm 2 (range 0-2292 cells/mm 2) , and the mean corneal thickness was 554.12 ± 22.77 microns (range 524-616 microns) in FECD patients. No correlation was found using a multivariate correlation analysis between endothelial cell count to corneal thickness and post operative visual acuity results for all ranges (distance, intermediate and near), (R 2 = 0.65, P = 0.18). The aged-matched control group consisted of 57 healthy eyes of 57 patients who had cataract surgery and implantation of similar presbyopia-correcting IOLs (n = 57). We analyzed two subgroups of IOLs separately: EDOF IOLs (9 eyes of FECD patients and 27 eyes of the control patients) and multifocal IOLs (10 eyes of FECD patients and 30 eyes of the control patients).
The demographic and ocular characteristics of the FECD patients and the control group before surgery were similar for the overall group as well as for the subgroups, except for shallower anterior chamber depth among the FECD patients in the multifocal IOL subgroup (3.18 ± 0.27 vs. 3.44 ± 0.34, respectively; P = 0.04). This can be explained by the trend toward older age in that subgroup, as the lens volume increases with age (68.8 ± 10.26 vs.62.4 ± 9.25; P = 0.054; Table 2).
There was no significant difference in visual acuity between the FECD eyes the matched healthy control eyes for all distances (Table 4, Fig. 1).

Astigmatism
The FECD patients in the EDOF-toric IOL subgroup, had higher preoperative and postoperative astigmatism compared with the control group (P < 0.001, P = 0.03, respectively, Table 5).
When calculating the astigmatism for the whole EDOF IOL subgroup (toric and non toric IOLs), the FECD patients had a trend toward higher preoperative corneal astigmatism magnitude (2.52 ± 1.86 and 1.18 ± 0.75, respectively; P = 0.08), and were implanted with a higher number of toric IOLs compared to the control (Table 3). There was no difference in the postoperative residual refractive astigmatism magnitude between the FECD patients and the healthy control group implanted with EDOF IOLs (0.53 ± 0.4 and 0.42 ± 0.35, respectively; P = 0.52).
In the multifocal-toric IOL subgroup, there was no difference in the preoperative and postoperative astigmatism between the FECD and the control groups (P = 0.73 and P = 0.13, respectively, Table 5).
When calculating the astigmatism for the whole multifocal IOL subgroup (toric and non toric IOLs), there was a higher preoperative corneal astigmatism magnitude in FECD patients (1.13 ± 0.27 and 0.72 ± 0.57, respectively; P = 0.002), and they were implanted with a higher number of toric IOLs compared to the control group (Table 3). There was no difference in the postoperative residual refractive astigmatism magnitude between FECD and the control patients implanted with multifocal IOLs (0.45 ± 0.28 and 0.43 ± 0.34, respectively; P = 0.61). Questionnaire EDOF IOLs. Nine FECD patients (100%) and 15 control patients (85%) completed the post-operative questionnaire. There was no difference in visual acuity perception between the FECD patients and the control group for all the ranges (distance, P = 0.36; intermediate, P = 0.75; near, P = 0.87; Fig. 2A), as well as no difference in spectacle independence for the distance (P = 0.18) and near ranges(P = 0.43) (Fig. 2B). The control patients   Fig. 2F). However, it did not disturb their daily life activities, and the general satisfaction was similar between the groups (P = 0.16 and P = 0.28, respectively; Fig. 2F). The mean follow-up time for the FECD group was 2.8 ± 1.8 years (range 1.25-7 years). None of the patients required corneal transplantation or IOL exchange during the follow-up period.

Discussion
In this study, we found that implantation of presbyopia-correcting IOLs (EDOF and multifocal IOLs), during routine cataract surgery in patients with grade 2 to 5 FECD, who are not candidates for corneal transplant, can be carefully considered. The results were slightly inferior compared with healthy age-matched eyes.
Viberg et al. 11 performed a large, population-based study of 33,741 patients (based on data from the Swedish National Cataract Registry), and included 893 patients with guttae who underwent cataract surgery. Both FECD and control patients had improved corrected distance visual acuity and self-assessed visual outcomes. However, the patients with guttae had inferior objective visual acuity, as well as inferior self-assessed visual outcomes in comparison with the control group with healthy eyes (P < 0.001). Watanabe et al. 12 found that the area of the corneal guttae was correlated to the corrected distance visual acuity, contrast sensitivity, and intraocular stray FECD patients demonstrated a trend toward higher preoperative corneal astigmatism magnitude in the EDOF subgroup (P = 0.08) and higher preoperative corneal astigmatism magnitude in the multifocal group (P = 0.002). However, with implantation of toric IOLs, the postoperative residual refractive astigmatism magnitude in both the EDOF IOLs and the multifocal IOLs groups were similar for the FECD and the control patients (P = 0.52, P = 0.61, respectively). The only subgroup with higher residual refractive astigmatism was the EDOF-toric-IOL subgroup, in which the postoperative refractive astigmatism among FECD patients was significantly higher compared with the healthy controls (P < 0.001 vs. P = 0.03, respectively; Table 5). It may explain the inferior UDVA (P = 0.007), and the better UNVA (P = 0.001) among the FECD patients implanted with EDOF IOLs, and www.nature.com/scientificreports/ be attributed to the EDOF-toric-IOLs subgroup that had higher postoperative residual astigmatism, and hence a mild myopic refraction. However, these differences were probably not clinically significant, as reflected by similar reported visual perception for all ranges between the groups. In the EDOF IOLs subgroup, the FECD patients reported less spectacle independence for intermediate range (P = 0.01) and overall (P = 0.006), although the objective visual acuity results were similar (P = 0.50). This may be related to the limitations of the objective visual acuity examinations in demonstrating parameters such as contrast sensitivity and color contrast. The FECD patients implanted with EDOF IOLs did not have more photopic phenomena compared to the control group, and none of them reported halos and glare "often" or "all the time" (P = 0.36, Fig. 2C).
Results reported in the literature are inconsistent regarding halos and glare in EDOF IOLs compared to monofocal IOLs. A European, multicenter, prospective study found that 4 months after cataract surgery, 51 of 68 patients (75%) implanted with EDOF IOLs did not have halos and glare, using a halos and glare simulator 13 . Another study based on data from the US FDA premarket approval trials, found more halos and glare with multifocal and EDOF IOLs compared to monofocal IOLs 14 . Finally, in a meta-analysis by Liu et al. 15 , two studies found no significant difference in halos and glare between EDOF and monofocal IOLs, while another US FDA study of 295 eyes implanted with TECNIS Symfony EDOF and monofocal lenses, found more frequent halos and glare in EDOF compared to monofocal IOLs.
In the multifocal IOLs subgroup, there was no difference in the objective visual acuity, post-operative mean spherical equivalent, visual acuity perception and spectacle independence between the Fuchs and control patients for all ranges (Fig. 1D-F, Fig. 2D-E). However, the rate of positive dysphotopsia was significantly higher in the Fuchs patients compared to the healthy controls (P = 0.006, Fig. 2F). As many as 75% of the FECD patients implanted with multifocal IOLs experienced halos and glare "often" or "all the time". However, none reported that it disturbed their daily life activity "often" or "all the time", and there was no significant difference in the overall satisfaction between the groups (Fig. 2F).
It is well-described that multifocal IOLs can cause significant photic phenomena and reduced night vision, even among healthy patients [16][17][18][19] . Wilkins et al. 20 conducted a randomized trial comparing monovision to multifocal IOLs after bilateral cataract surgery in 187 eyes, and found that 43% of the healthy patients who were implanted with multifocal IOLs, reported "annoying" or "debilitating" dysphotopsia, as compared to 18% in the monovision group (P < 0.001). These findings are similar to our own experience in healthy eyes. Using the same questionnaire and setup, we found that more than a third of the healthy patients implanted with trifocal IOLs reported photic phenomena "often" or "all the time" 21 .
In our study, the percentage of photopic phenomena in the FECD patients implanted with multifocal IOLs is higher than that described in the literature for healthy eyes 20,21 . It is reasonable to assume that the combination of corneal pathology with the known halos and glare limitation of multifocal IOLs may exacerbate the photic phenomena in the FECD patients more than in the healthy eyes. Nevertheless, as mentioned, none of the patients reported that it interfered significantly with daily life activities, and no IOL was exchanged.
A recent study reported the results of presbyopia-correcting IOLs after descemet membrane endothelial keratoplasty (DMEK) in FECD patients 22 . In this study, the median time between DMEK and the cataract surgery was 5 months, and it was offered as an alternative to combined endothelial keratoplasty and cataract surgery, or as an alternative to cataract surgery before endothelial keratoplasty. The authors reported better postoperative refractive results when DMEK was performed before cataract surgery, because the biometry measurements and IOL calculations were more accurate after the corneal guttae and edema were removed.
Indeed, there is ongoing concern regarding the need for future corneal transplant in FECD patients due to the cataract surgery or due to the natural history and progress of the FECD that may jeopardize the effectiveness of the presbyopia-correcting IOL. Viberg et al. 23 assessed the incidence rate of corneal transplantation after phacoemulsification based on data from 276,362 cataract patients from the Swedish National Cataract Registry. Among Table 5. Preoperative and postoperative astigmatism in patients with PC-toric-IOLs. D diopters. www.nature.com/scientificreports/ 3338 patients with corneal guttae, 152 (4.6%) underwent corneal transplantation, and among 188,915 patients without corneal guttae, 141 (0.1%), underwent corneal transplantation. Although the relative risk for corneal transplantation after phacoemulsification was 68.2 times higher in patients with corneal guttae, as compared to healthy controls, more than 95% of the patients with corneal guttae did not require corneal transplantation, during a 7-year follow-up. Moreover, progress in lamellar corneal transplant surgery led to minimal influence on the patients' refractive status. These findings raise a discussion regarding implantation of presbyopia-correcting IOLs in FECD patients 24 . This discussion should be conducted carefully, with full disclosure of the inferiority of the results in comparison to the general healthy population and the increased incidence of photic phenomena.
To optimize the results and to avoid presbyopia-correcting IOLs in eyes that are candidates for keratoplasty, Van Cleynenbreugel et al. 25 recommended evaluating the central corneal thickness and backscatter at the basal epithelial layer, preoperatively. They claim that it can help predict the need for future endothelial keratoplasty. In our study, none of the patients required corneal transplantation during a mean follow-up of more than two and a half years.
The limitations of the current study include its small sample size (the statistical power based on post hoc power analysis was only 0.6), and its retrospective nature. Due to the small sample size, IOLs with different optical characteristics (bifocal and tri-focal) were analyzed together in the multifocal subgroup. Furthermore, the preoperative and postoperative astigmatism was higher among FECD patients implanted with EDOF-toric-IOLs (Table 5), and more toric-IOLs were implanted in FECD patients, as compared to the control group. Additionally, we did not examine the CDIVA and the CDNVA, which could have eliminated the postoperative refractive error, especially in the EDOF-toric-IOLs group that had significantly higher residual astigmatism and more myopic refraction. We also included two eyes of each FECD patient when we could, as opposed to only one eye of each healthy control, in order to increase the sample size, and it could have affected the subjective visual acuity results by confounding between fellow eyes.
In conclusion, while the FECD patients implanted with EDOF IOLs had inferior UDVA and less spectacles independence, they did not have more photic phenomena compared with the healthy control eyes. The contrary was found in the multifocal IOLs subgroup with similar UDVA and spectacle independence results, but significantly more photic phenomena, in the FECD patients, compared with the healthy control eyes. This information can help tailor IOL selection for different individuals with different needs. However, caution should be taken with extrapolating our results to other presbyopia-correcting IOLs that were not investigated in this study. The FECD patients in both subgroups reported high general satisfaction, similarly to the control group, as indicated by their responses to the question of whether they would choose the same IOL again. Therefore, presbyopia-correcting IOLs can be carefully considered in patients with FECD, without corneal edema, who are not candidates for corneal transplantation, with the above-mentioned reservations. A large, randomized control study is warranted to support our findings.